Passive tumor targeting of renal-clearable luminescent gold nanoparticles: long tumor retention and fast normal tissue clearance

Abstract

Glutathione-coated luminescent gold nanoparticles (GS-AuNPs) with diameters of ∼2.5 nm behave like small dye molecules (IRDye 800CW) in physiological stability and renal clearance but exhibit a much longer tumor retention time and faster normal tissue clearance, indicating that the well-known enhanced permeability and retention effect, a unique strength of conventional NPs in tumor targeting, still exists in such small NPs. These merits enable the AuNPs to detect tumor more rapidly than the dye molecules without severe accumulation in reticuloendothelial system organs, making them very promising for cancer diagnosis and therapy.

Figure 1

Passive tumor targeting of renal clearable probes. A) The scheme of passive tumor targeting of renal clearable probes. In vivo tumor targeting and clearance kinetics can be measured by fluorescence imaging in real time after intravenous (IV) injection of the probes into nude mice. B) Schematic representation of the structures of glutathione coated NIR emitting gold nanoparticle (GS-AuNP; core size: 2.5 nm; hydrodynamic diameter: 3.3 nm) and the chemical structure of IRdye 800CW.

Figure 2

In vivo and ex vivo NIR fluorescence imaging of MCF-7 tumor-bearing mice IV injected with GS-AuNPs and IRdye 800CW. A) Representative in vivo NIR fluorescence images collected at p.i. time points of 0.5, 3, and 12 hr, respectively. The tumor areas were indicated with arrows. B, C) Ex vivo fluorescence images of organs and tumors taken from the MCF-7 tumor-bearing mice IV injected with GS-AuNPs (B) and IRdye 800CW (C) at the time points of 1 and 12 hr p.i., respectively. In each image: 1, tumor; 2, liver; 3, lung; 4, spleen; 5, heat; 6, kidney (left); 7, kidney (right). More images related to the tumor targeting of the IRdye 800CW were shown in Figure S5.

Figure 3

Quantitative analysis of passive tumor targeting of GS-AuNPs and IRdye 800CW. A) Contrast index (CI) of GS-AuNPs and IRdye 800CW at different p.i. time points showing that the NP reach the maximum CI value faster than the dye molecule. To reach the CI threshold value (CI = 2.5) for a potential imaging probe, it took 3.1 ± 0.2 and 8.2 ± 0.6 hr for the NP and the dye molecule, respectively. B) Retention kinetics in normal tissue showing the retention half-lives of GS-AuNPs and IRdye 800CW are 43.4 ± 6.6 min and 2.3 ± 0.3 hr (n = 3), respectively. C) Tumor targeting kinetics of GS-AuNPs and IRdye 800CW, respectively. D) Pharmacokinetics of the renal clearable GS-AuNP and IRdye 800CW after the IV injection in 24 hr, respectively. The curves of pharmacokinetics were fitted to biexponential decay equation with R-Square values of 0.9711 and 0.9838 for GS-AuNP and IRdye 800CW, respectively. The distribution half-lives (t_1/2α) of GS-AuNP and IRdye 800CW are 5.4 ± 1.2 and 6.3 ± 2.5 min, respectively. The elimination half-lives (t_1/2β) of GS-AuNP and IRdye 800CW are 8.5 ± 2.1 and 0.98 ± 0.08 hr, respectively (Data presented as mean ± SD, n = 3).

Figure 4

Biodistribution analysis of the passive tumor targetting in MCF-7 tumor-bearing mice. The biodistributions of GS-AuNPs (A), IRdye 800CW (B), and BSA-AuNPs (C) at 1 and 12 hr p.i., respectively. D) The ratios of the probe concentration in tumor to that in liver at 1 and 12 hr p.i., respectively.